Raltitrexed

Names

[ Name ]:
Raltitrexed

[Synonym ]:
N-[5-[N-[(3,4-dihydro-2-methyl-4-oxy-6-quinazolinyl)-methyl]-N-methylamino]-2-thenoyl]-L-glutamic acid
2kce
ZD1694
L-Glutamic acid, N-[[5-[[(1,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-
N-[(5-{methyl[(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl]amino}thiophen-2-yl)carbonyl]-L-glutamic acid
N-[(5-{Methyl[(2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl]amino}-2-thienyl)carbonyl]-L-glutamic acid
Raltitrexed
D1694
ICI-D 1694
MFCD00864168
N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid
Tomudex
2tsr
N-[[5-[[(1,4-Dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl]methylamino]-2-thienyl]carbonyl]-L-glutamic acid
ICI D1694
N-[(5-{Methyl[(2-methyl-4-oxo-1,4-dihydro-6-quinazolinyl)methyl]amino}-2-thienyl)carbonyl]-L-glutamic acid

Biological Activity

[Description]:

Raltitrexed is an antimetabolite drug used in chemotherapy, acting by inhibiting thymidylate synthase.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Nucleoside Antimetabolite/Analog

Signaling Pathways >> Apoptosis >> Thymidylate Synthase

Research Areas >> Cancer

[In Vitro]

Raltitrexed inhibits HepG2 proliferation by arresting the cell cycle at G0/G1, and the cell cycle is mediated via downregulation of cyclin A and CDK2[1]. Raltitrexed (0.1, 0.5, 2.5 μg/mL) decreases the viability of SGC7901 cells in a dose- and time-dependent manner. Raltitrexed (0.5 μg/mL) shows typical apoptotic morphology, including nuclear shrinkage, fragmentation, chromatin condensation and apoptotic bodies in SGC7901 cells. Raltitrexed blocks the cell cycle at the G0/G1 phase, decreases in the mitochondrial membrane potential. Raltitrexed also increases the level of ROS, induces caspase-3-dependent apoptosis via activation of the mitochondria, and increases TS protein and mRNA expression levels[3]. Raltitrexed (1.5 nM) reduces the number of GM00637 cells, selectively induces gene conversions, but does not affect DSB-induced HR or NHEJ[4].

[In Vivo]

Raltitrexed (0, 5, 10, 11.5, 13.5, 15 mg/kg b/w, i.p.) increases the rates of resorbed embryos and growth retardation of murine model of NTDs in a dose dependent manner. Raltitrexed (11.5 mg/kg b/w) maximally inhibits the thymidylate synthase (TS) activity in embryonic tissue, decreases dTMP levels and while increases dUMP levels[2].

[Cell Assay]

To assess the effect of Raltitrexed on cell viability and/or growth, GM00637 cells are plated into 25 cm2 flasks at a density of 3.3×105 cells per flask. Twenty four hours later, the medium is replaced with medium supplemented with various doses of Raltitrexed over a broad range of concentrations ranging from less than 1 nM to greater than 1 µM. Three flasks of cells are used for each dose tested. Cells are exposed to Raltitrexed for 24 hours, at which time the cells are refed with medium containing no Raltitrexed. Forty-eight hours after feeding with drug-free medium, cells are harvested and counted. The cell counts for the cells exposed to the various Raltitrexed doses are compared with the cell count for control cells not exposed to Raltitrexed as a measure of the impact of Raltitrexed on cell viability and/or growth rate.

[Animal admin]

The adult (7-8 week, 19-20 g) C57BL/6 mice are used in the experiment. Mice are maintained under 22°C with a 12 h light/day cycle and fed with standard mouse chow and tap water ad libitum. Female mice are mated with male overnight and vaginal plugs are examined in the following morning. The presence of vaginal plug in the pregnant mice is considered as gestational day 0.5. Pregnant mice are randomly divided into 6 groups with 10 mice in each group. Raltitrexed is dissolved in 0.9 % NaCl, and five groups are intraperitoneally injected with different doses of Raltitrexed (5, 10, 11.5, 13.5, 15 mg/kg b/w) on gestational day 7.5. The control group is intraperitoneally injected with 0.9 % NaCl at the same volume on gestational day 7.5. On gestational day 11.5, pregnant mice are sacrificed, and embryos are examined under dissect microscope.

[References]

[1]. Zhao H, et al. Raltitrexed Inhibits HepG2 Cell Proliferation via G0/G1 Cell Cycle Arrest. Oncol Res. 2016;23(5):237-48

[2]. Dong Y, et al. Raltitrexed's effect on the development of neural tube defects in mice is associated with DNA damage, apoptosis, and proliferation. Mol Cell Biochem. 2015 Jan;398(1-2):223-31.

[3]. Xue S, et al. Raltitrexed induces mitochondrial-mediated apoptosis in SGC7901 human gastric cancer cells. Mol Med Rep. 2014 Oct;10(4):1927-34.

[4]. Waldman BC, et al. Induction of intrachromosomal homologous recombination in human cells by raltitrexed, an inhibitor of thymidylate synthase. DNA Repair (Amst). 2008 Oct 1;7(10):1624-35.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.5±0.1 g/cm3

[ Melting Point ]:
176-1800C

[ Molecular Formula ]:
C₂₁H₂₂N₄O₆S

[ Molecular Weight ]:
458.488

[ Exact Mass ]:
458.126007

[ PSA ]:
180.93000

[ LogP ]:
-1.28

[ Index of Refraction ]:
1.692

[ Storage condition ]:
Hygroscopic, -20°C Freezer, Under Inert Atmosphere

Safety Information

[ Hazard Codes ]:
Xi: Irritant;

[ Risk Phrases ]:
R36/38

[ Safety Phrases ]:
S26-S36/37/39-S45-S25

[ RIDADR ]:
UN 3265 8/PG 2

[ WGK Germany ]:
3

[ Packaging Group ]:
II

[ Hazard Class ]:
8

Raltitrexed

Names

Biological Activity

Chemical & Physical Properties

Safety Information

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds